Composition and method of use for treating nausea and mental disorders using thiepin derivatives

ABSTRACT

The compounds are of the class of thiepin derivatives, more particularly thiepin derivatives, which may be substituted in the benzene rings by alkyl, alkoxy or alkylthio, further substituted in 11 positions by piperazinyl which may be fully substituted, and in 10-position by hydroxy or o-alkanoyl, and acid addition salts thereof. The compounds are useful as anti-emetic, anaesthesia-potentiating, reflex-inhibiting and catatonia inducing agents. An illustrative embodiments is 11-(4-methyl-1piperazinyl)-10,11-dihydrodibenzo(b,f)thiepin-10-ol.

United States Patent Schindler et a].

[4 1 Aug. 22, 1972 [72] Inventors: Walter Schindler, Riehen; Erich Schmid, Basel, both of Switzerland [73] Assignee: Ciba Geigy Corporation, Ardsley,

[22] Filed: March 30, 1970 [21] Appl. No.: 29,316

Related US. Application Data [62] Division of Ser. No. 702,828, Feb. 5, 1968, Pat.

[30] Foreign Application Priority Data Feb' 10, 1967 Switzerland ..2020/67 [52] US. Cl ..424/250, 424/244 [51] Int. Cl. ..A6lk 27/00 [58] Field of Search ..424/244, 250

[56] References Cited UNITED STATES PATENTS 3,356,680 12/1967 Schindler et al ..260/268 3,359,271 12/ 1967 Schlindler et al ..260/268 3,391,160 7/1968 Schlindler et a1 ..260/327 Primary Examiner-Stanley J. Friedman Assistant Examiner-Allen .1. Robinson Attorney-Karl F. Jorda and Bruce M. Collins [5 7] ABSTRACT The compounds are of the class of thiepin derivatives, more particularly thiepin derivatives, which may be substituted in the benzene rings by alkyl, alkoxy or alkylthio, further substituted in 11 positions by piperazinyl which may be fully substituted, and in l0-position by hydroxy or o-alkanoyl, and acid addition salts thereof. The compounds are useful as anti-emetic, anaesthesia-potentiating, reflex-inhibiting and catatonia inducing agents. An illustrative embodiments is l l-(4-methyl-1-piperazinyl)-10, l ldihydrodibenzo[b,f]ethiepin-10-01.

4 Claims, N0 Drawings the above-mentioned formula for eflecting anti-emetic,

COMPOSITION AND METHOD OF USE FOR TREATING NAUSEA AND MENTAL DISORDERS USING THIEPIN DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATION This is a divisional application of Ser. No. 702,828, filed Feb. 5, 1968, now U.S. Pat. No. 3,555,028.

DETAILED DISCLOSURE The present invention concerns new thiepin derival0 tives, processes for the production thereof, pharmaceutical preparations, which contain the new compounds and their use in warm-blooded animals. More particularly the present invention relates to compounds of the general Formula I wherein:

n is an integer of 2 or 3,

R is hydrogen or lower alkanoyl with up to seven carbon atoms,

X is hydrogen, lower alkyl, hydroxyalkyl or benzyl,

Y and Z are hydrogen, halogen preferably fluorine,

chlorine and bromine, lower alkyl, lower alkoxy or lower alkylthio, as well as their addition salts with inorganic or organic acids.

Particularly valuable compounds according to the invention are those wherein R is hydrogen or lower alkanoyl with up to seven carbon atoms; n is an integer of 2 or 3; X is methyl, 2-hydroxyethyl, or benzyl; and Y and Z each independently are hydrogen, chlorine, lower alkoxy or lower alkylthio, and pharmaceutically acceptable acid addition salts thereof.

Furthermore, the present invention relates to novel methods and compositions containing a compound of anaesthesia-potentiating, reflex-inhibiting and catatonic activities in warm-blooded animals, especially mammals. More particularly, the method of effecting such pharmacological activities in mammals is concerned with administering a compound as defined in the above-described formula in therapeutic doses.

According to this invention the scope of the substituents as defined in the above-mentioned formula may be characterized as follows:

The term lower alkyl as used herein alone or in lower alkoxy, lower alkylthio and lower alkanoyl means straight or branched alkyl chains of the general formula C ll wherein m represents an integer of 7 or less. More particularly in the compounds of general formula I, R, as alkanoyl group having at most 7 carbon atoms can be, e.g. the forrnyl, acetyl, propionyl, 2-methyl-propionyl, butyryl, 2-methyl-butyryl 3-methyl-butyryl, valeryl, 2-methyl-valeryl, 3- methyl-valeryl, hexanoyl, 2-methyl-hexanoyl, 3- methyl-hexanoyl, pivaloyl or the heptanoyl group.

X, as low alkyl group, can be, e.g. the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or the sec. butyl group, and as hydroxyalkyl group it can be, e.g. the 2- hydroxyethyl, 3-hydroxypropyl or the 2-methyl-3- hydroxy-propyl group.

Y and Z can be either identical or different, and, as substituents of the benzene rings, can be in the 1-, 2-, 3- or 4- and 6-, 7-, 8- or 9- position, the 2- and 8- positions being preferred. As low alkyl groups they represent, e.g. the methyl, ethyl, propyl, isopropyl, butyl or the isobutyl group; as low alkoxy group they represent e.g. the methoxy, ethoxy, propoxy, isopropoxy, butoxy or the isobutoxy group; and as low alkylthio groups they represent, e.g. the methylthio, ethylthio, propylthio, butylthio or the isobutylthio group.

To produce the new compounds of general Formula I, the carbonyl group in a compound of general Formula II wherein n, X, Y and Z have the meanings given in Formula I, is reduced to the hydroxy group, if desired, a compound obtained of general Formula I the radical OR of which is a hydroxy group, is acylated to form one the radical OR of which represents an alkanoyloxy group having at most seven carbon atoms, and if desired, a compound obtained of the general Formula I is converted into an addition salt with an inorganic or organic acid.

The reduction of the carbonyl compounds to the corresponding hydroxy compounds which can be in the cis or trans form, may be performed with the aid of complex metal hydride, in particular with lithium aluminum hydride. Also, for example, sodium borohydride, potassium borohydride or lithium borohydride can be used as well as complex metal hydride.

It is advantageous to use the complex metal hydrides in a solvent. Suitable solvents are, e.g. for lithium aluminum hydride: ether-type liquids such as ether, tetrahydrofuran, dioxane, dibutyl ether, di-isopropyl ether, butylethyl ether or diethylene glycol diethyl ether; for lithium borohydride: ether-type liquids such as ether and tetrahydrofuran; for sodium and potassium borohydride: alkanols such as methanol or ethanol, optionally with the addition of an ether-type liquid and/or of water, e.g. methanol/water, methanol/ether or methanol/dioxane/water.

In addition, other boron compounds such as diborane or diisoarnyl borane can be used for the reduction according to the invention. These reducing agents are preferably used dissolved in an ether-type liquid. Tetrahydrofuran, in which diborane dissolves easily, is particularly suitable.

Moreover, a compound of general Formula H may be reduced with a metal alcoholate in the corresponding alkanol or also in a hydrocarbon such as toluene or xylene. This reduction is optionally performed under an atmosphere of nitrogen. Aluminum isopropylate is a particularly suitable reducing agent. A reaction temperature of about 20145 is maintained during the reaction.

The hydroxy group of compounds of general Formula I wherein the radical OR is a hydroxy group can be acylated, for example, by heating them in the anhydride of a low alkanoic acid such as acetic acid, propionic acid, butyric acid, pivalic acid or enanthic acid. In addition, the corresponding carboxylic acid halides such as chlorides or bromides can be used for this acylation instead of the anhydrides; these are used advantageously in the presence of an acid binding agent. Suitable acid binding agents are, e. g. tertiary bases such as triethylamine. Instead of the hydroxy compounds of general Formula I, also alkali metal derivatives, e.g. sodium derivatives, of such compounds can be reacted with corresponding acid halides.

The starting compounds of general Formula II are described in the literature.

The compounds of general Formula I obtained according to the process of the present invention are then converted, if desired, into their addition salts with inorganic and organic acids in the usual way. For example, the acid desired as salt component or a solution thereof is added to a solution of a compound of general Formula l in an organic solvent. Preferably organic solvents in which the salt formed is difficultly soluble are chosen for the reaction so that it can be isolated by filtration. Such solvents are, e.g. methanol, acetone, methylethylketone, methanol/ether or ethanol/ether. Instead of free bases, pharmaceutically acceptable acid addition salts can be used, i.e. salts with those acids the anions of which are non-toxic in the usual dosages. It is also of advantage when the salts to be used as compositions crystallize well and are not or are only slightly hygroscopic. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, B-hydroxyethane sulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid or mandelic acid, for example, can be used for salt formation with compounds of the general Formula I.

As pointed out above, the compounds of the present invention, i.e. compounds of the above-described general formula and their physiologically tolerable acid addition salts possess valuable pharmacological and therapeutic properties and may be used in the form of pharmaceutical compositions, especially as antiemetic, anaesthesia-potentiating, reflex-inhibiting and catatonia inducing agents. According to the pharmacological tests, the compounds of the present invention may be used for the treatment of insomnia, agitation, anxiety, and mental disorders like psychoneurosis, schizophrenia and manic conditions. The antiernetic properties of some of the instantly claimed compounds offer utility in motion sickness, post-operative vorniting, gastro-intestinal disorders, i.e. in all kinds of nausea.

The toxicity of the compounds of the instant invention is low: for instance, the LD of 2-chloro-1l-[4-(2- hydroxyethyl)- l -piperazinyl]- 1 0, 1 1 dihydro dibenzo[b,t']thiepin-l0-ol administered orally to mice is higher than 800 mg./kg.; the LDM of 8-chloro-1 1-(4- methyl-1-piperazinyl)-l0,l l-dihydro dibenzo[b,f]t hiepin-lO-ol in mice is higher than 200 mg./kg. i.p.; the LD, of 2-chloro-1 1-( 4-methyl-1-piperazinyl)-l0,l ldihydro dibenzo[b,f]thiepin--ol methane sulfonate is higher than 80 mg./kg. on intravenous administration to mice.

The compounds possess a general quietening effect on animals that can be seen in the motility test and in the potentiation of a short-acting anaesthetic; this effeet is further substantiated by the adrenolytic effect on the isolated seminal vesicle. The latter test being correlated with a decrease in activity in the intact animal. The tests were performed as described in greater detail in the following paragraphs.

According to the test described by C. Morpurgo et al.: Psychopharmacologia 6. 178-191 (1964), the dosage of which a decrease of 50 percent of motility over the control group is determined (expressed as DE on administration of the following compounds:

Test

Compound Animals Administered DB mgJkg. i.p.

2-Chloro-l l-(4-methyll piperazinyl)-10,1 1-dihydro dibenzo[b,f]thiepin- 10-01 2-Chlorol l-(4-methyl-1- piperazinyl)- l 0,1 l-dihydro dibenzo[b,f]thiepinl0-ol methane sulfonate 8-Chloro-1l-(4-methyl-lpiperazinyl)-10,l l-dihydro dibenzol b,f]thiepin- 10-01 about 1 .3 mice about 1 .4 mice about 1 .5 mice According to a method described by W. Theobald et al.: Archint. Pharmacodym 148, 560-596 (1964) and W. Theobald et al.: Arzneirnittelforschung 9, 285-286 (1959) the extent to which anaesthesia induced by a standard amount of the anaesthetic, 4-alkyl-2-methoxy phenoxyacetic acid diethyl amide, is prolonged by a known dose of test compound. The change in the duration of the anaesthetic effect was calculated in per cent of the effect observed with the control group; the results are given below:

% increase in sleeping time Test Animal Dosage mg./kg. s.c.

Compound Administered 2-Chloro- 1 l-(4-methyl- 1-piperazinyl)-l0,11- dihydro dibenzo[b,f]- thiepin- 10-01 Z-Chlorol l-(4-methyll-piperazinyl)-10,1 1- dihydro dibenzo[ b,f]thiepin- 1 0-01 methane sulfonate 20 mice l mice l ,600

ing table (17 regitin equals 1).

Compound Test Adrenolytic Administered Animal Value 2-Chloro-1 1-(4-methyll-piperazinyl)-10,1 1- dihydro dibenzo[ b,f] thiepin- 1 O-ol Z-Chloro-l l-(4-methyl- 1-piperaziny|)-10,l l-

guinea pig about 0.45

dihydro dibenzol[b,f]- guinea pig about 0.30 thiepin-lO-ol methane sulfonate mg./kg.

Compound Administered 2-Chloro-l l-( 4-methyll-piperazinyl)-l0,l 1- dihydro dibenzo[b,f]- thiepin-l -01 2-chloro-l l-(4-methyll-piperazinyl)- 10,1 1- dihydro dibenzo[b,f]- thiepin-lO-ol methane sulfonate DE mg/Kg about 2.5

about 3.5

The compounds of the present invention may be used in warm-blooded animals, particularly mammals, in form of pharmaceutical compositions containing the compounds in admixture or conjunction with a pharmaceutical organic or inorganic solid or liquid carrier for oral, rectal or parenteral administration. The total daily doses for mammals vary from about 0.1 mg./kg. to about 200 mg./kg., preferably about 0.15 mg./kg. to about 150 mg./kg. depending on the mammal and condition. The preferred route of administration is the oral route. Suitable compositions include, without limitation, tablets, capsules, powder solutions, suspensions, sustained release formulations and the like.

Suitable dosage units such as dragees (sugar-coated tablets), tablets, suppositories or ampoules, preferably contain 5 50 mg of an active substance according to the invention or a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain between 1-90 percent of a compound of the general formula I or a pharmaceutically acceptable salt thereof as active substance. They are produced by combining the active substance with, e.g., solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

Other dosage units suitable for oral administration are hard gelatine capsules and also soft capsules made of gelatine and a softener such as glycerine. The hard gelatine capsules preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulphite (Na S- O or ascorbic acid. In

soft gelatine capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilizers can also be added.

Examples of dosage units for rectal administration are suppositories which consist of a combination of an active substance or a suitable salt thereof with a fatty foundation, or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols.

Ampoules for parenteral, particularly intramuscular, administration preferably contain a water soluble salt of an active substance in a concentration of, preferably, 0.5 5 percent, in aqueous solution, optionally together with suitable stabilizing agents and buffer substances.

The following prescriptions further illustrate the production of tablets and dragees:

a. 250 g. of 2-chloro-11-(4-methyl-1-piperazinyl)- 10,1 1-dihydro-dibenzo[b f]thiepin-l0-ol methane sulphonate are mixed with 175.80 g. of lactose and 169.70 g. of potato starch, the mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicium dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing mg and containing 25 mg of active substance. If desired the tablets can be grooved for better adaptation of the dosage.

b. A granulate is produced from 250 g of 2-chlor0- l l-(4-methyl- 1 -piperazinyl)-10,l l-dihydro-dibenzo[ b,f]thiepin-10-ol methane sulphonate, 175.90 g. of lactose and the alcoholic solution of 10 g. of stearic acid. After drying, the granulate is mixed with 56.60 g. of colloidal silicium dioxide, 165 g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate and the mixture is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made of 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestuff and g. g of titanium dioxide and dried. The dragees obtained each weigh mg. and contain 25 mg. of active substance.

The following examples illustrate the production of the new compounds of general Formula 1 and the preparation of pharmaceutical compositions without limiting the scope of the invention. The temperatures are given in degrees centigrade.

EXAMPLE 1 17.0 g. of 11-(4-methyl-l-piperazinyl)-dibenzo[b,f]t hiepin-10(l lH)-one are dissolved in 60 ml. of abs. tetrahydrofuran and a suspension of 4.0 g. of lithium aluminum hydride in 50 ml. of abs. tetrahydrofuran are added dropwise to the 10-20 warm solution within 15 minutes. The reaction mixture is refluxed for 6 hours, then cooled to 20 and 7 ml. of water are added drop wise. The precipitate obtained is filtered off and washed with tetrahydrofuran. The filtrate is dried over calcium chloride, evaporated in vacuo and the residue is recrystallized from acetic acid ethyl ester. The pure 1 l -(4-methyl-l-piperazinyl)-10, l l -dihydrodibenzo[b,f]thiepin-l0-ol obtained melts at 153.5 1 56.

EXAMPLE 2 a. 17.9 g. of 2-chloro-11-(4-methyl-1-piperazinyl)- dibenzo-[b,f]thiepin-l( 1 lH)-one dissolved in 150 ml. of abs. tetrahydrofuran are added dropwise within 30 minutes at 20 30 to a suspension of 4 g of lithium aluminum hydride in 80 ml. of abs. tetrahydrofuran. The reaction mixture is refluxed for hours, cooled to 20, 8 ml. of water are carefully added and the product is worked up analogouslyvto Example 1. The crude product obtained is recrystallized from propanol, whereupon the pure 2-chloro-11-(4-methyl-l-piperazinyl)-10,1l-dihydro-dibenzo[b,flthiepin--01 melts at 196 201.

b. To produce the corresponding 10-ol-propionate compound, 9.6 g. of the 2-chloro-11-(4-methyl-lpiperazinyl)- l 0, 1 1-dihydro-dibenzo[b,f]thiepin-10-01 obtained according to (a) are dissolved by heating in 100 ml. of abs. pyridine and 5.2 g. of propionic acid anhydride (in 50 percent excess) are added to the solution obtained. The reaction mixture is left to stand overnight and is then carefully concentrated. The residue is dissolved in cold water, the solution obtained is extracted three times with ether, the combined ether extracts are washed with water, dried with calcium chloride and concentrated on a water bath. The residue is dissolved in 40 ml of methylethyl ketone and the solution obtained is made acid to congo paper with alcoholic hydrochloric acid whereupon the pure, water soluble dihydrochloride of 2-chloro-11-(4-methyl-1- piperazinyl)- 1 0, 1 1 -dihydro-dibenzo[b,f]thiepin-10-01 propionate melts at 153-155.

c. The free base obtained according to (a) may be converted into the methane sulphonate as follows: 5 g. of the free base are dissolved in 300 ml. of boiling methylethyl ketone, 1.33 g. of methane sulphonic acid are added to the solution obtained while stirring, the mixture is left to stand for 16 hours, the precipitated crystals are removed, washed with methylethyl ketone and dried in vacuo at 60. A colorless powder is obtained, M.P. l9l-l92, which completely dissolves in water. The aqueous solution has a weakly acid reaction.

EXAMPLE 3 8-chloro-l l-(4-methyl-l-piperazinyl)-10,1 1- dihydro-dibenzo [b,f]thiepin-l0-ol, M.P. l75-1 7 7, is obtained analogously to example 2 starting from 20 g. of 8-chloro-l 1-( 4-methyl- 1 -piperazinyl)-dibenzo[b,fl thiepin-l0(11H)-one and 4,5 g. of lithium aluminum hydride.

EXAMPLE 4 17.7 g. of 2-methoxy-11-(4-methyl-1-piperazinyl)- dibenzo[b,f]-thiepin-10(l1H)-one are dissolved while warming in 80 ml. of abs. tetrahydrofuran. This solution is added dropwise at l020 to 4 g. of lithium aluminum hydride in 60 ml. of tetrahydrofuran, the reaction vessel being occasionally cooled. The mixture is then refluxed for 3 hours, cooled to 20 and 8 ml. of water are added. The crude product obtained is worked up analogously to Example 1 and recrystallized from acetic acid ethyl ester whereupon pure 2-methoxy-11- 4-methyll -piperazinyl )-l 0,1 l-dihydro-dibenzo[ b,f]thiepin-10-ol is obtained, M.P. 156-l 602.

The methane sulphonate may be prepared from the free base: 7.6 g. of the free base are dissolved in 300 ml. of methylethyl ketone at 2.26 g. of methane sulphonic acid are added to the solution while stirring whereupon the crystalline methane sulphonate precipitates. This is filtered ofl under suction and dried in vacuo at 60. The methane sulphonate melts at 153l 56 and dissolves easily in water. The aqueous solution has a weakly acid reaction.

EXAMPLE 5 2-chloro-l 1-[4-(2-hydroxyethyl)- l-piperazinyl1- 10,11-dihydro-dibenzo[b,f]thiepin-10-ol, M.P. 164-168 (from nitromethane) is obtained analogously to Example 1 starting from 2-chloro-l 1-[4- (2-hydroxyethyl l -piperazinyl] -dibenzo b,f] thiepin- 10(1 lH)-one, M.P. 157-161, with lithium aluminum hydride.

EXAMPLE 6 2 g. of 2-methoxy-1l-(4-methyl-hexahydro-1H-1,4-

diazepin-l-yl)-dibenzo[b,f]thiepin-10( l 1H)-one are dissolved in 30 ml. of abs. tetrahydrofuran and the solution obtained is added dropwise to a stirred suspension of 1 g. of lithium'aluminum hydride in 50 ml of abs. tetrahydrofuran. The reaction mixture is refluxed for 3 hours at 60 70 and then 2 ml. of water are added dropwise. The precipitate formed is filtered off under suction and washed with tetrahydrofuran. The filtrate is concentrated and the residue is recrystallized from acetonitrile. The pure 2-methoxy-l1-(4-methyl-hexahydro- 1H- 1 ,4-diazepinl -yl)- l 0, l l-dihydrodibenzo[b,f]thiepin- 10-01 obtained melts at 134-13 7.

EXAMPLE 7 EXAMPLE 8 20 g. of 2-chloro-l l-(4-benzyl-1-piperazinyl)- dibenzo[b,f]thiepin-10(l1H)-one are dissolved in ml. of abs. tetrahydrofuran. The solution obtained is added dropwise to a stirred suspension of 4.5 g. of lithium aluminum hydride in 30 ml of abs. tetrahydrofuran and the reaction mixture is refluxed for 4 hours. After working up the product as described in Example 1, it is recrystallized from acetonitrile. Pure 2-chloro-l1-(4- benzyl- 1 -piperazinyl 1 O, l 1-dihydro-dibenzo[ b,f]thiepin-10-ol is obtained, M.P. l l4l 17.

EXAMPLE 9 S-methylthio- 1 l 4-methyll -piperazinyl l 0, 1 l dihydro-dibenzo-[b,f]thiepin-l0-ol is obtained analogously to Example 1 starting from 8-methylthio- 9 l 1-(4-methyl-1-piperazinyl)dibenzo[b,f]thiepin- 10(1 lH)-one by reduction with lithium aluminum hydride. After recrystallization from alcohol, it melts at EXAMPLE 10 250 g. of 2-chloro-11-(4-methyl-l-piperafinyl)- 10,1l-dihydro dibenzo-[b,f]thiepin-l-ol, 175.8 g. of lactose and 169.7 g. of potato starch are mixed, the

mixture is moistened with an alcoholic solution of g.

of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.5 g. of magnesium stearate and 32 g of colloidal silicon dioxide are mixed thereto and the mixture is pressed into 10,000 tablets each weighing 100 mg. and containing 25 mg. of the active thiepinol. If desired, the tablets can be grooved to enable better adaptation of the dosage instructions.

EXAMPLE 11 25 0 g. of 8-chloro-1 l-(4-methyll -piperazinyl 10,1 l-dihydro dibenzo-[b,f]thiepin-10-ol is worked up and pressed into tablets as described in Example 10.

EXAMPLE 12 EXAMPLE13 10 mg. to 200 mg. of 2-chloro-ll-(4-methyl-lpiperazinyl l 0, l l-dihydro dibenzo[b,f]thiepin- 1 0-0] methane sulfonate are introduced into a two-piece gelatine NO. 1 capsule.

We claim:

1. A therapeutic composition for producing antiemetic effects comprising a pharmaceutical carrier and an anti-emetically effective amount of a compound of the formula R is hydrogen or lower alkanoyl with up to seven carbon atoms;

X is hydrogen, lower alkyl, lower hydroxyalkyl or benzyl;

Y and Z each independently are hydrogen, fluorine,

chlorine, bromine, lower alkyl, lower alkoxy, or

lower alkylthio; and

n is an integer of 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, in dosage unit form acceptable for internal administration.

2. A method for treating a mammal suffering from nauseacomprising administering to said mammal an anti-emefically efl'ective amount of a compound as defined in claim 1.

3. A method of producing catatonic effects in a mammal comprising administering a catatonically effective amount to said mammal of a compound as defined in claim 1.

4. A method for treating a mammal suffering from insomnia, agitation, anxiety, psychoneurosis, schizophrenia or manic conditions comprising administering to said mammal an effective amount for treating the above conditions of a compound as defined inclaim l. 

2. A method for treating a mammal suffering from nausea comprising administering to said mammal an anti-emetically effective amount of a compound as defined in claim
 1. 3. A method of producing catatonic effects in a mammal comprising administering a catatonically effective amount to said mammal of a compound as defined in claim
 1. 4. A method for treating a mammal suffering from insomnia, agitation, anxiety, psychoneurosis, schizophrenia or manic conditions comprising administering to said mammal an effective amount for treating the above conditions of a compound as defined in claim
 1. 